Figure 1. Role of dofetilide and L-type calcium current on the APD and APD dispersion prolongations.

Figure 2. Role of dofetilide and L-type calcium current on the EADs appearance in the ECG and the intracellular calcium release.

Introduction: Dofetilide is a class III drug whose use needs to be monitored due to the possible occurrence of Torsades de Pointes (TdP). The mechanisms are unclear but research suggests that both early after depolarizations (EADs) and increased dispersion of the action potential duration (APD) might be involved. Importantly, drug-induced TdP is more common in women, possibly due to higher L-type calcium current (ICaL) levels. Our goal is to investigate pro-arrhythmic mechanisms of dofetilide in human using computer simulations. We will assess the effect of dofetilide on the APD dispersion and prolongation, EADs formation and the intracellular calcium concentration ([Cai]) for various doses and ICaL levels. Methods: A transmural human ventricular model was constructed including endocardial, midmyocardial and epicardial cells. We use the monodomain model to describe the electrical wave in the tissue and the Grandi et al model (1) to describe the membrane kinetics. Dofetilide-induced HERG block formulation was included to the ionic model following (2). The computational domain was stimulated with different frequencies 2Hz,1Hz and 0.5Hz at the endocardium and the electrophysiological activity was simulated for various dofetilide doses [D]=0 to 120 nM and for ICaL from fCaL=100 to 140% of control. All the results that we show correspond to the simulation with 1Hz frequency Results: In agreement with experimental recordings (3), in control (fCaL=100%), dofetilide increases APD by 20% and APD dispersion by 20-30ms but no EADs are observed. EADs appearance depends on both parameters [D] and fCaL. Fixing one and increasing the other results in EADs appearance. Panel C (resp D) shows the role of the dose dofetilide (resp ICaL) on the EADs genesis. EADs result in long APD of up to 1200 ms (panel A) and importantly, increased APD dispersion of up to 300 ms (panel B) due to transmural differences in EADs durations. EADs are also observed in the pseudo-ECG for different dofetilide doses (panel E) and levels of fCaL (panel F). Their appearance could be explained by a spontaneous calcium release. In fact plotting the intra-cellular calcium concentration shows that EADs appearance in panel E (resp B) is synchronized with an intra-cellular calcium release panel G (resp H). The magnitude of the EADs in the pseudo-ECGs is also scalable with the released calcium concentrations. Conclusions: ICaL is a key modulator of dofetilide-induced EADs in human ventricular tissue. A combination of high dofetilide doses and L-type calcium current is responsible for the EADs appearence. Importantly, EADs cause a significant increase in APD dispersion, which might provide the substrate for the establishment of reentry and TdP.